title: 5-Nitro-2-furfuriliden derivatives as potential anti-Trypanosoma cruzi agents: design, synthesis, bioactivity evaluation, cytotoxicity and exploratory data analysis.
abstract: The anti-Trypanosoma cruzi activity of 5-nitro-2-furfuriliden derivatives as well as the cytotoxicity of these compounds on J774 macrophages cell line and FN1 human fibroblast cells were investigated in this study. The most active compounds of series I and II were 4-butyl-[N'-(5-nitrofuran-2-yl) methylene] benzidrazide (3g; IC50=1.05μM±0.07) and 3-acetyl-5-(4-butylphenyl)-2-(5-nitrofuran-2-yl)-2,3-dihydro,1,3,4-oxadiazole (4g; IC50=8.27μM±0.42), respectively. Also, compound 3g was more active than the standard drugs, benznidazole (IC50=22.69μM±1.96) and nifurtimox (IC50=3.78μM±0.10). Regarding the cytotoxicity assay, the 3g compound presented IC50 value of 28.05μM (SI=26.71) against J774 cells. For the FN1 fibroblast assay, 3g showed IC50 value of 98μM (SI=93.33). On the other hand, compound 4g presented a cytotoxicity value on J774 cells higher than 400μM (SI >48), and for the FN1 cells its IC50 value was 186μM (SI=22.49). Moreover, an exploratory data analysis, which comprises hierarchical cluster (HCA) and principal component analysis (PCA), was carried out and the findings were complementary. The molecular properties that most influenced the compounds' grouping were ClogP and total dipole moment, pointing out the need of a lipophilic/hydrophilic balance in the designing of novel potential anti-T. cruzi molecules.
authors.affiliation: Department of Biochemical and Pharmaceutical Technology, Faculty of Pharmacy, University of São Paulo, Av. Prof. Lineu Prestes, 580, São Paulo, SP 05508-000, Brazil. palaceberlf@usp.br
authors.forename: Fanny
authors.initials: F
authors.lastname: Palace-Berl
authors.forename: Salomão Dória
authors.initials: SD
authors.lastname: Jorge
authors.forename: Kerly Fernanda Mesquita
authors.initials: KF
authors.lastname: Pasqualoto
authors.forename: Adilson Kleber
authors.initials: AK
authors.lastname: Ferreira
authors.forename: Durvanei Augusto
authors.initials: DA
authors.lastname: Maria
authors.forename: Rodrigo Rocha
authors.initials: RR
authors.lastname: Zorzi
authors.forename: Leandro
authors.initials: L
authors.lastname: de Sá Bortolozzo
authors.forename: José Ângelo Lauletta
authors.initials: JÂ
authors.lastname: Lindoso
authors.forename: Leoberto Costa
authors.initials: LC
authors.lastname: Tavares
mesh_terms: D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D016000:Cluster Analysis; D015195:Drug Design; D006801:Humans; D051379:Mice; D056004:Molecular Dynamics Simulation; D010069:Oxadiazoles / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D025341:Principal Component Analysis; D055672:Static Electricity; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D014349:Trypanosoma cruzi / Q000187:drug effects*
chemical_list: D010069:Oxadiazoles; D014344:Trypanocidal Agents
keywords: 5-Nitro-2-furfuriliden; Azomethine derivatives; Molecular modeling; Nifuroxazide; Oxadiazoline derivatives; Trypanosoma cruzi